Identification of Autoantibodies to a Hybrid Insulin Peptide in Type 1 Diabetes

Wenzlau, Janet M.; Gu, Yong; Michels, Aaron; Rewers, Marian; Haskins, Kathryn; Yu, Liping

doi:10.3390/diagnostics13172859

Cited by 5 publications

(1 citation statement)

References 33 publications

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“…Insulin autoantibodies are frequently the first to emerge in young children, followed sequentially by any of the others (islet antigen 2 (IA-2), glutamic acid decarboxylase 65 (GAD-65) and zinc transporter 8 (ZnT8). At clinical onset, 95% of patients have antibodies to at least one of these beta cell proteins ( 11 ). Several factors play a part in determining the susceptibility of an individual towards the loss of immunologic self-tolerance, including age, sex, genetics, and specific environmental exposure.…”

Section: Mechanismsmentioning

confidence: 99%

Immunological and virological triggers of type 1 diabetes: insights and implications

Lemos,

Hirani,

von Herrath

2024

Front. Immunol.

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Type 1 diabetes (T1D) is caused by an autoimmune process which culminates in the destruction of insulin-producing beta cells in the pancreas. It is widely believed that a complex and multifactorial interplay between genetic and environmental factors, such as viruses, play a crucial role in the development of the disease. Research over the past few decades has shown that there is not one single viral culprit, nor one single genetic pathway, causing the disease. Rather, viral infections, most notably enteroviruses (EV), appear to accelerate the autoimmune process leading to T1D and are often seen as a precipitator of clinical diagnosis. In support of this hypothesis, the use of anti-viral drugs has recently shown efficacy in preserving beta cell function after onset of diabetes. In this review, we will discuss the various pathways that viral infections utilize to accelerate the development of T1D. There are three key mechanisms linking viral infections to beta-cell death: One is modulated by the direct infection of islets by viruses, resulting in their impaired function, another occurs in a more indirect fashion, by modulating the immune system, and the third is caused by heightened stress on the beta-cell by interferon-mediated increase of insulin resistance. The first two aspects are surprisingly difficult to study, in the case of the former, because there are still many questions about how viruses might persist for longer time periods. In the latter, indirect/immune case, viruses might impact immunity as a hit-and-run scenario, meaning that many or all direct viral footprints quickly vanish, while changes imprinted upon the immune system and the anti-islet autoimmune response persist. Given the fact that viruses are often associated with the precipitation of clinical autoimmunity, there are concerns regarding the impact of the recent global coronavirus-2019 (COVID-19) pandemic on the development of autoimmune disease. The long-term effects of COVID-19 infection on T1D will therefore be discussed, including the increased development of new cases of T1D. Understanding the interplay between viral infections and autoimmunity is crucial for advancing our knowledge in this field and developing targeted therapeutic interventions. In this review we will examine the intricate relationship between viral infections and autoimmunity and discuss potential considerations for prevention and treatment strategies.

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Section: Mechanismsmentioning

confidence: 99%

Immunological and virological triggers of type 1 diabetes: insights and implications

Lemos,

Hirani,

von Herrath

2024

Front. Immunol.

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A structural basis of T cell cross-reactivity to native and spliced self-antigens presented by HLA-DQ8

Tran,

Lim,

Loh

et al. 2024

Journal of Biological Chemistry

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Proinsulin C-peptide is a major source of HLA-DQ8 restricted hybrid insulin peptides recognized by human islet-infiltrating CD4+ T cells

Bhattacharjee,

Pakusch,

Lacorcia

et al. 2024

PNAS Nexus

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Type 1 diabetes (T1D) is an autoimmune disease that develops when T cells destroy the insulin-producing beta cells that reside in the pancreatic islets. Immune cells, including T cells, infiltrate the islets and gradually destroy the beta cells. Human islet-infiltrating CD4+ T cells recognize peptide epitopes derived from proinsulin, particularly C-peptide. Hybrid Insulin peptides (HIPs) are neoepitopes formed by the fusion of two peptides derived from beta-cell granule proteins and are known to be the targets of pathogenic CD4+ T cells in the NOD mouse and human islet-infiltrating CD4+ T cells. Proinsulin is widely recognized as a central antigen in T1D, but its role in forming HIPs is unclear. We developed a method to functionally screen TCRs derived from human islet-infiltrating CD4+ T cells and applied this to the identification of new proinsulin-derived HIPs. We generated a library of 4,488 candidate HIPs formed by fusion of proinsulin fragments and predicted to bind to HLA-DQ8. This library was screened against 109 islet-infiltrating CD4+ T-cell TCRs isolated from four organ donors who had T1D. We identified 13 unique HIPs recognized by 9 different TCRs from two organ donors. HIP specific T-cell avatars responded specifically to a peptide extract from human islets. These new HIPs predominantly stimulated CD4+ T-cell proliferation in PBMCs from individuals with T1D in contrast to HLA-matched controls. This is the first unbiased functional, islet-infiltrating T-cell based, screen to identify proinsulin derived HIPs. It has revealed many new HIPs and a central role of proinsulin C-peptide in their formation.

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Identification of Autoantibodies to a Hybrid Insulin Peptide in Type 1 Diabetes

Cited by 5 publications

References 33 publications

Immunological and virological triggers of type 1 diabetes: insights and implications

Immunological and virological triggers of type 1 diabetes: insights and implications

A structural basis of T cell cross-reactivity to native and spliced self-antigens presented by HLA-DQ8

Proinsulin C-peptide is a major source of HLA-DQ8 restricted hybrid insulin peptides recognized by human islet-infiltrating CD4+ T cells

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